Efficacy and safety of eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with anthracycline/taxanes

Abstract Background This prospective real‐world study aimed to assess the efficacy and safety of eribulin in the clinical practice against advanced breast cancer (ABC) in China. Patients and Methods In this study, eligible patients with inoperable locally advanced or metastatic breast cancer who had experienced prior neo−/adjuvant or failed the palliative treatment with anthracycline/taxanes were included. Eribulin (1.4 mg/m2) was infused intravenously on Day 1 and Day 8 every 3 weeks until disease progression or intolerable toxicity occurred. The progression‐free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety of the treatment were assessed. Results One hundred and thirty‐four patients were enrolled. The median PFS (mPFS) was 4.3 months (95% CI: 0.3–15.4). The ORR and DCR was 32.1% and 79.1%, respectively. The mPFS of patients who received eribulin as first‐ or second‐line treatment was significantly better than those who received eribulin as ≥3‐line treatment (6.9 months [95% CI: 3.2–8.8] vs. 4.0 months [95% CI: 3.4–4.6], p = 0.006). The mPFS of patients with triple‐negative, HER2‐positive, and HER2(−)/HR(+) was 3.4 (95% CI: 2.7–4.1), 6.2 (95% CI: 2.3–10.1) and 5.0 months (95% CI: 4.1–5.9), respectively. HER2(+) patients had significantly longer PFS than TNBC patients (p = 0.022). Patients received combination therapy had a significantly longer mPFS than those who received eribulin monotherapy (5.0 months [95% CI 3.6–6.3] vs. 4.0 months [95% CI: 3.3–4.7] [p = 0.016]). Multivariate analysis revealed that MBC patients with a molecular typing of non‐TNBC receiving eribulin as ≤2‐line therapy and combination therapy had a low risk of disease progression. Neutropenia (33.58%), leukopenia (11.94%), and thrombocytopenia (4.48%) were the most common treatment‐related adverse events. Conclusion Eribulin demonstrated effective clinical activity and a favorable tolerability profile in Chinese patients with ABC in the real‐world. The efficacy and safety profile were consistent with those reported in previous randomized phase 3 trials.


| INTRODUCTION
][6] Despite advancements in the treatment, the 5-year survival rate of breast cancer is only 26%. 7[10][11] Eribulin, a nontaxane microtubule dynamics inhibitor, has shown promise in improving the OS of breast cancer patients who had failed previous taxanes treatments.The EMBRACE study (Study-305), involving 762 patients with locally recurrent/metastatic breast cancer (MBC), have demonstrated that eribulin treatment can extend OS by approximately 2.5 months compared with the physician's choice of treatment (median OS [mOS]: 13.1 vs. 10.6 months, HR = 0.81, p = 0.041). 12In Study-301, the result showed that eribulin did not achieve a significant improvement in OS (mOS: 15.9 vs. 14.5 months; p = 0.056) compared with capecitabine in overall population.However, there was a significant survival benefit in TNBC patients, where eribulin significantly extend the mOS by 5 months and reduced the risk of death by 29.8%. 13Based on the findings of these studies, eribulin has been approved as a subsequent-line treatment for MBC.
Eribulin, as a non-paclitaxel microtubule dynamic inhibitor, offers therapeutic benefits in paclitaxel-resistant patients by binding to high-affinity sites distinct from taxanes.This binding leads to the formation of nonfunctional protein polymers, irreversible mitosis blocking, and cell death. 14][17] The widespread utilization of eribulin in clinical practice, along with previous studies highlighting its value in combination therapy for MBC, [18][19][20][21] underscores the need to extend the conclusions from clinical trials, which often exclude certain patient populations, to real-world settings.This prospective real-world study was conducted to evaluate the efficacy and safety of eribulin in Chinese patients with ABC in routine clinical practice, providing a valuable reference for the clinical application of eribulin real-world settings.

| Patients and treatment
This study was a prospective, non-randomized, observational trial.Patients aged between 18 and 75 years with inoperable locally advanced or MBC were eligible.Patients had previously undergone prior neo−/adjuvant or palliative treatment with anthracycline/taxanes and experienced disease progression.Other key inclusion criteria included the presence of at least one measurable lesion, ECOG PS 0 ~ 2, and sufficient organ reserve function with no obvious treatment contraindications.
Eribulin (1.4 mg/m 2 ) was infused intravenously on Day 1 and Day 8 every 3 weeks until disease progression (PD) or intolerable adverse reactions.Imaging evaluation such as computed tomography or magnetic resonance imaging scans was performed every two cycles, Blood analyses and physical examinations were conducted before administration of eribulin on Days 1 and 8 of each cycle.As an observational study, investigators had the discretion to decide whether or not to combine other drugs.Systemic treatment initiated beyond 12 months after neo-/adjuvant chemotherapy was defined as the first-line therapy.

| Outcomes
The efficacy assessment included progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR).PFS was defined as the time from the first administration of eribulin to PD, according to RECIST version 1.1 or death from any cause.ORR was calculated as the proportion of patients with complete or partial response (CR or PR) while DCR was the sum of CR, PR, and stable disease (SD).Adverse events (AEs) were assessed according to the NCI Common Terminology Standard for Adverse Events (CTCAE5.0).

| Statistical methods
Descriptive statistics were used to summarize patents' characteristics and safety data.Kaplan-Meier (K-M) curves were utilized to illustrate PFS along with the corresponding 95% confidence intervals (95% CI), while the log-rank tests were used to assess differences between groups.Additionally, univariate and multi-factor analyses were performed to identify factors related to the effectiveness of eribulin; patients were categorized by the following criteria, line of therapy at the initiation of eribulin (≤2-line vs. >2line), molecular typing (TNBC vs. non-TNBC), presence of visceral metastasis (with or without), liver metastasis (with or without), number of metastases (≤2 vs. >2), combination therapy (yes or no), and ECOG PS (≤1 vs. 2).Variables with p < 0.05 were included in multivariate Cox regression analysis.All statistical analyses were performed using IBM SPSS26.0.

| Univariate and multivariate analyses for the predictors of PFS
Univariate analysis revealed that factors including line of therapy at initiation of eribulin, molecular type, liver metastasis, multiple metastases, combination therapy, and ECOG PS were significantly clinical variables associated with PFS when patients received eribulin therapy.Multivariate Cox regression analysis indicated that patients with non-TNBC, eribulin as ≤2line treatment and eribulin combination therapy showed a significantly longer PFS than patients with TNBC, eribulin as >2line treatment and eribulin monotherapy.The other variables analyzed did not reach prognostic significance for PFS (Table 4).

| DISCUSSION
To further evaluate the efficacy and safety of eribulin in breast cancer, this prospective real-world study enrolled 134 patients with ABC.The mPFS for all patients was 4.3 months, which was consistent with previous phase III clinical trials with larger sample size (mPFS: 3.7-4.2months) 12,13,22 and real-world studies (mPFS: 3.61-5.064][25][26] The ORR in our study was 32.1%, which was higher than those in EMBRAC study (12.0%) and Study 301 (11.0%). 12,13The higher ORR in this study may be attributed to approximately 66% of patients receiving combination therapy, which likely improved the antitumor activity compared with eribulin monotherapy.Combination therapy with eribulin plus trastuzumab or pertuzumab in HER-2(+) ABC patients resulted in an ORR of 34.8%. 27Another phase II clinical trial, the ORR of combining eribulin with gemcitabine reported an ORR of 37.3%. 28he study findings also indicated that eribulin treatment was more effective when used in earlier lines of therapy.The ORR of eribulin as first-or second-line treatment (54.0%) was significantly better than that eribulin as ≥3 lines treatment (20.0%).Furthermore, patients receiving eribulin as the first-or second-line treatment had significantly longer mPFS compared to those receiving eribulin as ≥3line treatment (mPFS: 6.9 months vs. 4.0 months, respectively).Interestingly, the OS improvement with eribulin in the routine clinical practice appeared to be more notable than that observed in clinical trials.In the first real-world, community-based study of mTNBC conducted in the United States, 252 subjects were divided into two groups based on their prior systemic treatment lines: an early use group (≤2 lines) and a late use group (≥3 lines).In the early use group, the mOS was reported to be 23.0 months, which was obviously longer than the mOS reported in EMBRACE and Study-301(13.1 months and 14.4 months, respectively) trials although the data from different studies could not be compared directly.For patients in the late-line use group, who had more metastatic sites and received more previous systemic treatments, the mOS was 14.7 months. 12,13,29Another multicenter retrospective analysis showed that a significantly better mOS for patients with ≤2 previous chemotherapy lines was compared with those with >2 previous chemotherapy lines (328 vs. 264 days), 30 Oruc et al. investigated the factors influencing the outcomes of eribulin treatment in 80 patients with MBC who had experienced 3-10 prior lines of treatment.Their multivariate COX analysis revealed that previous systemic treatment line was an independent prognostic factor affecting PFS.The mPFS in patients with three prior lines of treatment was 8.6 months, compared to 4.6 months in those >3 prior lines of treatment. 31t is well-known that molecular typing is an important prognostic factor in ABC.Two phase II studies indicated that combing eribulin with HER-2-targeted agents in HER2(+) ABC could result in a PFS of about 9.2-11.6months with tolerable toxicity. 20,32However, patients with HER2(+) in our study had an obviously inferior mPFS (6.2 months) compared with those reported in previous studies, which may be attributed to that most of HER2(+) patients were heavily pretreated and received eribulin monotherapy.A recent real-world study from United Kingdom revealed that patients with TNBC had a significantly worse prognosis than HER2(+)/ER(+) patients when treated with eribulin. 30e expression of hormone receptors is also an independent factor affecting PFS of patients with ABC.Rossi et al showed that HR(+) patients had almost twice as long PFS as HR(−) patients (mPFS: 2.9 vs. 1.4 months, p = 0.0051). 33Sirven et al. demonstrated that patients with TNBC had significantly shorter PFS than those with HR-positive tumors (mPFS: 3.3 vs. 4.5 months). 23imilar results were found in another real-world study (TNBC vs. HR(+) mPFS =3.4 vs. 2.0 months, p = 0.003). 33n our study, there was significant difference in PFS between the HER2+ and TNBC groups (mPFS = 6.2 vs. 3.4 months, p = 0.022), while the difference between TNBC and HER2(−)/ HR(+), or between HER2(+) and HER2(−)/ HR(+) were not statistically significant.Multivariate COX analysis demonstrated that TNBC was one of adverse prognostic factors for PFS of eribulin therapy.
In our study visceral metastasis, liver metastasis and multiple metastases were not key prognostic factors for PFS of patients with MBC.Some studies have found that the development of visceral metastasis usually predicts poor survival outcomes, especially for those with liver and/or lung metastases. 34,35Dell'Ova et al. found that pulmonary metastasis (HR = 1.53 [95% CI: 1.16-2.02])was one of the independent prognostic factors affecting TTF in ABC patients treated with eribulin. 36Similarly, an observational study in Japan showed that liver metastasis resulted a poor TTF in HER2(−) ABC. 37The result of our study showed that patients with or without visceral metastasis had no significant difference in mPFS benefit (4.0 [95% CI: 3.3-4.7]vs. 4.5 months [95% CI: 3.7-5.2],p = 0.56), which may be partly attributed to the lower proportion of enrolled patients without visceral metastasis (Figure 2C).Although univariate analysis showed that patients without liver metastasis had a longer mPFS than that of patients with liver metastasis (mPFS: 4.6 months [95% CI: 3.2-5.9]vs. 4.0 months [95% CI 3.4-4.5])(Figure 2D).Multivariate Cox analysis found that liver metastasis was not an independent significant prognostic factor for PFS (Table 4).De Sanctis et al. found that the number of metastatic lesions was negatively correlated with PFS in the treatment of eribulin. 38The results of a multicenter retrospective study showed that multiple metastases were correlated with poor PFS, patients with 1-2 metastatic sites had a mPFS of 5.3 months while the mPFS of those with ≥3 metastatic sites was 3.6 months (p = 0.023). 39In our study, patients with ≤2 metastatic sites also achieved a mPFS of 4.6 months, significantly longer than that in patients with ≥3 metastatic sites (4.0 months, p = 0.044) (Figure 2E).However, multivariate Cox regression analysis indicated that the number of lesions did not reach prognostic significance for PFS.The investigation of eribulin combination therapy is attracting increasing attention.In the ERIGE study, eribulin plus gemcitabine yield an ORR of 37.3% in the treatment of TNBC.The mPFS and mOS were 5.1 and 14.5 months, respectively.Subgroup analysis showed that BRCA wildtype patients had better curative effect. 28A similar result was observed in our study, patients who received eribulin plus other chemotherapy agent had a better mPFS and ORR compared to those who received eribulin monotherapy (ORR: 47.8% vs. 19.6%p = 0.004, mPFS: 7.0 months (95% CI: 5.1-9.0) vs. 4.0 months (95% CI: 3.3-4.7),p = 0.001) (Figure 2G).In a single-arm, multicenter, phase II study, the combination of eribulin and trastuzumab achieved an ORR of 71.2% in the first-line treatment of HER2(+) MBC, and the mPFS was 11.6 months. 32The JBCRG-M03 study indicated that the treatment regimen containing eribulin, pertuzumab, and trastuzumab was effective and generally well tolerated in the first-or second-line treatment of HER2(+) ABC with a mPFS of 9.2 months (95% CI: 7.0-11.4months). 20Based on this study, a phase III study evaluating the triple combination of eribulin, pertuzumab, and trastuzumab in patients with Her2(+) ABC has been carried out. 21A phase II study aimed to evaluate the efficacy and safety of eribulin plus anlotinib in patients with ABC; the mPFS of the experimental group and the control group was 5.1 versus 3.5 months, respectively (HR = 0.56, 95% CI: 0.32-0.98). 40In our study, 88 patients received eribulin combination therapy, and the mPFS of the eribulin monotherapy and combination therapy was 4.0 and 5.0 months, respectively (Figure 2F).Multivariate Cox regression analysis found that eribulin combination therapy is a predictor of better specific PFS.
Many other studies have explored the relationship between ECOG PS score and the efficiency of eribulin.Zhao et al. found that patients with different performance status had similar PFS; the difference of mPFS between ECOG 0-1 and ECOG 2 group was not significant. 39Conversely, De Sanctis et al. confirmed that a worse ECOG PS was related to a worse PFS. 38In our multivariate Cox regression analysis, there was no significant difference in PFS according to performance status (ECOG PS 0-1 vs. ECOG PS 2).
Several retrospective studies have demonstrated the safety of eribulin in breast cancer.The most common toxicities (all grades) included fatigue, nausea, neutropenia, and peripheral neuropathy, with neutropenia being the most common high grade (≥3) AE. 37,41 Although the majority of patients in our study received the elibulin combination therapy, the overall toxicity was tolerable.Hematological toxicity was the most common AEs, with grade 3/4 neutropenia and leukopenia were recorded in 33.58% and 11.94% of patients, respectively.Fatigue and nausea were the most common non-hematological toxicities.Other AEs included diarrhea, constipation, oral mucositis, and stomachache.
Our study has some limitations.Firstly, this study lacked the non-eribulin treated patients for comparison and the sample size was limited.As a real-world study, potential confounders may introduce bias to the results of the prognostic analysis.The evaluation of eribulin related AEs was partly based on subjective patient experience, such as peripheral neuropathy, hand and foot syndrome, nausea, and vomiting.In addition, some patients completed the treatment in the outpatient department, leading to missing data on some AEs may be missing.The OS data were not mature due to limited follow-up time, and the follow-up is still ongoing to provide more clinical data on eribulin in Chinese patients with ABC.

| CONCLUSION
In conclusion, this study demonstrated the effectiveness and tolerability of eribulin in patients with ABC in realworld setting.Non-TNBC, eribulin as ≤2lines treatment and combination therapy were related to the PFS benefit of the eribulin therapy.

F I G U R E 1
Progression-free survival in ABC patients receiving eribulin.T A B L E 2Overall efficacy evaluation all of patients.
Demographics and clinical characteristics of patients.

response Combine therapy group (%) Eribulin monotherapy group (%)
Best tumor response between eribulin monotherapy and combination therapy group.Univariate and multivariate multi-factor analysis analyses for the predictors of PFS.Kaplan-Meier curves for PFS according to potential predictive factors: (A) Line of therapy at initiation of eribulin; (B) Molecular type; (C) Visceral metastases; (D) Liver metastases; (E) Number of metastatic sites; (F) eribulin monotherapy or combine therapy; (G) whether or not combine chemotherapy drug.
T A B L E 3 Adverse events.
T A B L E 5